tbuckley/cabot-search huggingface dataset:
CLIMATE: Assessing the clinical utility of miR-371a-3p as a marker of residual disease in stage 1 testicular germ cell tumour (TGCT) following orchiectomy: ANZUP 1906.
Authors: Ciara Conduit, Peter S. Grimison, Jeremy Howard Lewin, Aaron Richard Hansen, James F. Lynam, Andrew James Weickhardt, Phillip Parente, David Colin Campbell, Wei Hong, Gavin M. Marx, Orlaith Mary Heron, Anna Kuchel, Margaret Mary McJannett, Thomas Cusick, Antoinette Fontela, Sophie O Haire, Kristina Zlatic, Ian D. Davis, Ben Tran
Journal: Journal of Clinical Oncology (2023)

TPS5100 Background: There is impetus to identify biomarkers in TGCT to help select those at high-risk of relapse following orchiectomy and target interventions to prevent over-treatment. miR-371 has been shown to reliably predict presence of active malignancy with higher accuracy than currently available biomarkers. More clinical evidence is required to ascertain its clinical utility as a marker of microscopic disease to guide treatment recommendations in stage 1 TGCT and other settings. Methods: CLIMATE ANZUP1906 (ACTRN12622000247774) is a prospective, single-arm, non-interventional cohort study recruiting adults with clinical stage 1 TGCT entering active surveillance. Eligible participants are recruited within six weeks of orchiectomy and are willing to undergo active surveillance in accordance with the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group Surveillance Recommendations (or similar), without adjuvant treatment. Participants with metastases, non-testicular primaries, or history of contralateral TGCT are ineligible. Serum, plasma, and buffy coat samples are collected at consent and every three months until 24 months (and at relapse, if applicable). miR-371 will be assessed using established protocols. Clinical data, including treatment(s), surveillance, and relapses are captured in Australia’s national TGCT registry, iTestis. Archival tissue from diagnosis ± relapse is identified for future translational research. The primary endpoint for CLIMATE is 12-month relapse-free survival of miR-371 positive/negative groups. Key secondary endpoints include miR-371 during surveillance and at relapse, concordance between serum/plasma miR-371 and archival tissue, and health economic analyses. Prior studies suggest ~20% of post-orchidectomy miR-371 samples are positive. A sample size of 200 participants will result in 20 relapses, 160 non-relapses and 20 individuals lost to follow-up, and will permit description of the primary endpoint. Patient-level data from CLIMATE will contribute to a joint analysis of parallel trials evaluating miR-371 in this setting, COG AGCT1531 and SWOG1823. The first participant was recruited to CLIMATE in February 2022. 9/12 study sites in Australia and New Zealand have been activated and 47/200 (24%) have been enrolled. Recruitment is expected to take 36 months, followed by a further 24 months follow-up. Clinical trial information: ACTRN12622000247774 .
Comparison of Child-Turcotte-Pugh score and albumin bilirubin index score for advanced hepatocellular carcinoma at an LMIC tertiary cancer facility.
Authors: Nishant Sinha, Jasmine Porwal, Amit Sehrawat, Ruchi Mitra, Sumedha Gargy
Journal: Journal of Clinical Oncology (2023)

e16174 Background: Liver cancer, most commonly HCC, ranks third in cancer-related deaths. Hepatic dysfunction is a key factor in management. BCLC Staging uses CTP Score with objective biosynthetic and subjective parameters as ascites and encephalopathy. Albumin-bilirubin Index (ALBI) grade is an objective method of assessing hepatic dysfunction. Many studies have validated its predictive accuracy. The present study is an attempt to study the clinical profile, risk factor and to compare ALBI with CTP Score as a predictive marker of hepatic function in HCC. Methods: This is a prospective observational study from Feb 2022-Jan 2023. Patients with suspected HCC had physical examination and relevant lab investigations. Diagnosis is established with either appropriate imaging with raised AFP or by Histopathology. ECOG PS, CTP score, ALBI Grade, and BCLC Stage of HCC were assigned. Patients were treated accordingly and are being actively followed. The data was analysed using SPSS with appropriate statistical tests to study their clinical profile and the correlation between the two prognostic scores. Results: There were 54 new patients of HCC with 78.6% being males. Mean age of presentation was 60.88±10.6 yr, with majority had abdominal pain and distension. 78% were diagnosed on imaging with raised AFP. 31 had viral hepatitis with 19 having hepatitis B, and 12 Hepatitis C. 2 were HIV+ with Hepatitis B. 50% were alcoholic. 4 patients had active autoimmune conditions with 2 having RA, 1 had AIH and 1 having AS. 75% had cirrhosis with the majority having&gt;50% liver involvement,61% having portal vein and bile duct invasion. 10,28, and 11 patients belonged to CTP class A,B and C respectively. 57% fell to BCLC Stage 3. 5,21,28 patients belonged to ALBI Grade 1,2 and 3 respectively. The higher ALBI Index had poorer biochemical, radiological profiles and BCLC Stages, signifying the similarity in prognostic severity. Positive correlation found between the CTP score and the ALBI grade (r=0.339; P Value=0.012). Conclusions: The above study concluded ALBI Index as a good prognostic tool for HCC management in low and middle-income countries. It has only 2 biochemical parameters, can easily be done on a single visit and as it correlates significantly with CTP Score.[Table: see text]
Association of enhanced epithelial-mesenchymal transition signature with tumor microenvironment, angiogenesis, and survival in gastric cancer.
Authors: Masanori Oshi, Li Yan, Chikara Kunisaki, Itaru Endo, Kazuaki Takabe
Journal: Journal of Clinical Oncology (2023)

e16002 Background: Among the hallmarks of cancer, epithelial-mesenchymal transition (EMT) that epithelial cancer cells gain the characteristics of mesenchymal cells, is one of the key mechanisms of cancer cell metastasis. On the other hand, the clinical relevance of EMT that occurs in gastric cancer patients has not been clearly shown. Methods: To measure the level of EMT in gastric cancer, gene set variation analysis was used to score total of 807 gastric cancer patient samples from two independent large cohorts; TCGA and GSE84437. Results: EMT high gastric cancer was significantly associated with worse overall survival (hazard ratio (HR)=1.74, p=0.011 in the TCGA, and HR=2.01, p&lt;0.001 in the GSE84437), and the association was stronger with EMT signature score compared to expressions of each EMT-related genes, CDH1, CDH2, VIM, or FN1. EMT signature levels were not significantly different among gastric cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, and pancreatic ductal adenocarcinoma, and high level of EMT signature was associated with survival only in gastric cancer. Among the histological types, mucinous and diffuse type had high EMT level compared to tubular, papillary, or signet gastric cancer ( p&lt;0.001). EMT signature level was significantly correlated with tumor depth and AJCC stage (all p&lt;0.001), but not consistently with lymphatic metastasis. Interestingly, the EMT score was independent factor for patient survival including clinicopathological features, not only for overall survival but also disease-specific survival in the TCGA cohort (multivariate; p=0.006 and 0.032, respectively). EMT high gastric cancer was associated with low fraction of Th1 cells and high fraction of dendritic cells and M1 macrophages (all p&lt;0.001 in both cohort), but not with interferon-gamma immune response. EMT high gastric cancer tended to be inversely correlated with cell proliferation-related gene sets, and significantly associated with high infiltration fraction of stromal cells, including fibroblasts, adipocytes (all p&lt;0.001). On the other hand, they significantly enriched multiple pro-cancerous gene sets, such as TGF-β signaling, hypoxia, and angiogenesis, consistent with infiltration of angiogenesis-related stromal cells such as microvascular and lymphatic endothelial cells, and pericytes (all p&lt;0.001). These results were shown consistently in two large cohort; TCGA and GSE84437. Conclusions: EMT signature in a bulk tumor was associated with cancer aggravating pathways such as TGF-β signaling, hypoxia, and angiogenesis, as well as with worse survival in gastric cancer patients.
Early tumor shrinkage (ETS) as clinical factor to select maintenance with cetuximab (cet) monotherapy in patients (pts) with <i>RAS/BRAF </i>wild-type (wt) metastatic colorectal cancer (mCRC): A secondary endpoint analysis of the ERMES study.
Authors: Armando Orlandi, Carmine Pinto, Maria Alessandra Calegari, Nicola Normanno, Evaristo Maiello, Lorenzo Antonuzzo, Roberto Bordonaro, M. Giulia Zampino, Francesca Bergamo, Giuseppe Tonini, Stefano Tamberi, Antonio Avallone, Tiziana Pia Latiano, Gerardo Rosati, Antonio Pazzola, Alberto Ballestrero, Alberto Zaniboni, Vincenzo Formica, Carlo Barone
Journal: Journal of Clinical Oncology (2023)

3603 Background: ERMES study aimed to demonstrate non-inferior PFS of maintenance with cetuximab (cet) monotherapy (arm B) compared to FOLFIRI+cet until progression (arm A) in RAS and BRAF wt mCRC pts. Although study did not meet its primary endpoint it showed better toxicity profile and OS for cet alone and comparable ORR between arms. Here we present results of ETS, a secondary endpoint. Methods: ETS was defined as ≥20% reduction of the sum of target lesions at 8 weeks from the start of treatment, and was assessed by blinded independent central review. PFS and OS were compared between ETS+ and ETS- pts according to treatment arm in the modified Per-Protocol (mPP) population. Results: 327 of 337 (97%) pts were evaluable for ETS. In arm A, no statistically significant differences were observed between ETS+ and ETS- cohort for PFS (11.9 m, 95%CI 11.28-13.19, vs 12.2 m, 95%CI 10.82-14.93; HR 1.05, 95%CI 0.73-1.50; p 0.77) and OS (30.75 m, 95%CI 25.09-37.73, vs 25.46 m, 95%CI 19.96-34.63; HR: 0.79, 95%CI 0.50-1.24; p 0.29). In arm B, a statistically significant difference was observed between ETS+ and ETS- cohort for PFS (10.62 m, 95%CI 9.86-13.09, vs 8.52 m, 95%CI 7.89-9.37; HR 0.70, 95%CI 0.49-1.00; p 0.036) and for OS (38.88 m, 95%CI 34.53-43.25, vs27.43 m, 95%CI 20.59-36.64; HR 0.60, 95%CI 0.38-0.93; p 0.019). ETS+ pts reported no statistically significant difference between arm B and arm A in terms of PFS (HR 1.12, 95%CI 0.83-1.49; p 0.43) while experiencing a better OS for arm B compared to arm A (HR 0.72, 95%CI 0.50-1.05; p 0,08). Conclusions: In pts achieving ETS, induction treatment with FOLFIRI+cet may be de-escalated to cet alone without detrimental effect on PFS, resulting in less toxicity and better OS. These data support the hypothesis that ETS might be a clinical dynamic predictor of efficacy of a less intensive maintenance strategy, allowing to plan de-escalation to cet alone after 4 months of FOLFIRI+cet induction. Clinical trial information: NCT02484833 .
Utilization of germline testing in patients with early-onset pancreatic cancer (EOPC).
Authors: Hamid Ehsan, James Thomas Symanowski, Aly Athens, Katherine Wilson, Katie Tobik, Sara Elrefai, Mohamed E. Salem, Jimmy J. Hwang, Kunal C. Kadakia
Journal: Journal of Clinical Oncology (2023)

e16300 Background: EOPC is associated with significant life years lost. Approximately 5%-10% of pancreatic adenocarcinoma (PAC) have an underlying genetic predisposition and national guidelines recommend testing in all patients with PAC. Certain germline mutations such as BRCA2 and PALB2 predict response to specific treatments including platinum and targeted therapies. It is currently unknown to what extent patients with EOPC pursue recommended germline testing. We examined the utilization of germline testing in patients with EOPC who were referred to genetics. Methods: A retrospective review of patients with EOPC at the Levine Cancer Institute (LCI), defined as ≤60 years of age at time of diagnosis, who were referred and seen by genetics between January 2019 and December 2021 was performed. Germline testing was performed using multi-gene cancer panels. Positive germline testing was considered as any known pathogenic or likely pathogenic variant not including variants of unknown significance (VUS). Results: We identified 69 patients with EOPC who were evaluated by genetics. The median age was 55 years (range 25-60) with 36 (52%) male, 33 (48%) female, 48 (70%) white, 16 (23%) Black, 61 (89%) with ECOG 0-1, 36 (52%) current or prior smoking history, and 28 (42%) presenting with metastatic disease. As shown, out of 69 patients, 10 (14%) declined testing or had unknown results, 30 (43%) had negative germline testing, 29 (42%) had genetic testing that revealed 19 (65%) had VUS, and 10 (34%) had pathogenic variants. The most frequently seen pathogenic variants were ATM (30%), BRCA1 (30%), BRCA2 (10%), MLH1 (10%), RAD51C+ (10%) and CFTR (10%). Conclusions: Our data suggest that most patients with EOPC who are evaluated undertake germline testing. Given the predictive nature of certain pathogenic mutations on PAC treatment options, characteristics of patients with EOPC who decline testing should be further explored. There is need for larger studies to confirm the high incidence of pathogenic variants observed in our cohort of EOPC patients. [Table: see text][Table: see text]
A pilot study of liposomal irinotecan plus 5-FU/LV combined with paricalcitol in patients with advanced pancreatic cancer whose disease progressed on gemcitabine-based therapy.
Authors: Patrick Grierson, Rama Suresh, Benjamin R. Tan, Katrina Sophia Pedersen, Manik A. Amin, Haeseong Park, Nikolaos Trikalinos, Jingxia Liu, Kian-Huat Lim, Andrea wang-gillam, Sapana Prakashrao Bansod
Journal: Journal of Clinical Oncology (2023)

e16263 Background: 5-FU-based chemotherapy is the standard of care for patients with advanced pancreatic cancer progressed on gemcitabine-based therapy. Based on the NAPOLI-1 study, 5-FU/LV/liposomal irinotecan is currently an FDA-approved regimen in the second-line setting with median progression free survival (mPFS) 3.1 months, median overall survival (mOS) 6.1 months and objective response rate (ORR) 16%. In pancreatic cancer mouse models, vitamin D was shown to remodel the desmoplastic stroma and when combined with chemotherapy significantly improved animal survival. Methods: We conducted a pilot study in patients with advanced pancreatic cancer progressed on gemcitabine-based therapy treated with 5-FU (2,400mg/m 2 )/LV (400mg/m 2 )/liposomal irinotecan (70mg/m 2 ) with paricalcitol in two dose level cohorts: paricalcitol 75mcg IV on day 1 weekly (N=10, dose level 1) or 7mcg/kg IV on day 1 weekly (N=10, dose level 2). The primary endpoint was safety and toxicity. Dose-limiting toxicities (DLT) were assessed during cycle 1. Secondary endpoints include ORR, PFS and OS. Results: Between 8/29/2019 to 5/6/2021, a total of 20 patients were enrolled in the study. No DLTs or grade 4 adverse events were observed in either paricalcitol cohort. The most common toxicities were gastrointestinal (nausea, diarrhea), fatigue and anemia and were similar in both cohorts. Only one grade 3 adverse event was possibly due to paricalcitol (spinal fracture, dose level 1). 2/17 (12%) evaluable patients experienced an objective response (both in dose level 2), one of which was confirmed. Disease control rate (DCR) was 65%. Median follow up was 6.15 months. At the time of analysis, mPFS of all patients is 3.57 months (95% CI 1.28 – 8.12) and mOS is 6.14 months (95% CI 2.43 – 11.77). The mPFS is 3.55 months (0.79-6.21) for dose level 1 and 4.83 months (0.62-9.96) for dose level 2. The mOS is 6.15 months (0.79-8.12) for dose level 1 and 6.66 months (1.78-14.53) for dose level 2. Correlative analysis shows increased tumor vascularity (via CD31) and a trend toward decreased stromal fibrosis (via Sirius Red) in dose level 2. Conclusions: Administration of paricalcitol in combination with liposomal irinotecan and 5-FU/LV is well tolerated in patients with advanced pancreatic cancer and survival outcomes were comparable to liposomal irinotecan plus 5-FU/ LV. Clinical trial information: NCT03883919 .
Long-term outcomes with isatuximab-carfilzomib-dexamethasone (Isa-Kd) in relapsed multiple myeloma patients with 1q21+ status: Updated results from the phase 3 IKEMA study.
Authors: Thierry Facon, Philippe Moreau, Ivan Spicka, Kenshi Suzuki, Kwee Yong, Joseph Mikhael, Taro Fukao, Kamlesh Bisht, Nicole Armstrong, Sandrine Macé, Marie-Laure Risse, Thomas G. Martin
Journal: Journal of Clinical Oncology (2023)

8029 Background: Gain or amplification of 1q21 (1q21+, ≥3 copies), a chromosomal abnormality frequently observed in multiple myeloma (MM), has a negative impact on prognosis due to its potential involvement in resistance to MM therapy and disease progression. In the prespecified, long-term analysis of the Phase 3 IKEMA trial in relapsed MM patients (pts), treatment with Isa-Kd showed continued, significant improvement in progression-free survival (PFS) vs Kd (HR 0.58; 95.4% CI 0.42–0.79), with meaningful increase in depth of response (complete response or better [≥CR] 44.1% vs 28.5%; minimal residual disease negativity [MRD-] 33.5% vs 15.4%, MRD- ≥CR 26.3% vs 12.2%), and a manageable safety profile. In this subgroup analysis of IKEMA, we evaluated efficacy of Isa-Kd in pts with 1q21+ status (with or without high-risk chromosomal abnormalities [HRCA]) and related subgroups – isolated 1q21+ (≥3 copies without HRCA), gain(1q21), amp(1q21) – at long-term follow-up (44.2 months). Methods: Pts with 1–3 prior lines of therapy were randomized to Isa-Kd (n=179) or Kd (n=123). Assessment was prespecified (at 30% cut-off by FISH) for 1q21+ status as ≥3 copies, gain(1q21) as 3 copies, and amp(1q21) as ≥4 copies. Results: In the Isa-Kd and Kd arms, 41.9% and 42.3% of pts had 1q21+ status, 26.3% and 25.2% isolated 1q21+, 24.0% and 30.1% gain(1q21), 17.9% and 12.2% amp(1q21) respectively. Greater PFS benefit was achieved with Isa-Kd vs Kd in pts with 1q21+ status (HR 0.58, 95% CI 0.37–0.92) and in pts with isolated 1q21+, gain(1q21), or amp(1q21) (Table). Responses deepened by adding Isa to Kd, with increased rates of very good partial response or better (≥VGPR), ≥CR, MRD-, and MRD- ≥CR (Table). Conclusions: 1q21 abnormalities affect PFS in MM pts. Our results at long-term follow-up of pts with 1q21+ status (with or without HRCA) in the IKEMA study continue to show greater PFS benefit and deeper responses with Isa-Kd than Kd, consistent with the overall population and earlier 1q21+ subgroup interim analyses. Thus, they support Isa-Kd as an effective treatment option also for difficult-to-treat, 1q21+ pts with relapsed MM. Clinical trial information: NCT03275285.[Table: see text]
Preoperative oral antibiotic bowel preparation regimens in radical cystectomies with continent diversion.
Authors: Rishabh Simhal, Kerith Ruoyao Wang, Maria L. Poluch, Yash Shah, Joon Yau Leong, Mihir S. Shah, Leonard G. Gomella, Thenappan Chandrasekar, Costas D. Lallas
Journal: Journal of Clinical Oncology (2023)

e16610 Background: Bowel preparation regimens (BRs) were historically standard before radical cystectomy (RC) with urinary diversion to decrease infection and anastomotic breakdown. However, the Enhanced Recovery After Surgery protocol (ERAS) no longer includes BRs. Recent data show that BRs may exacerbate frailty, worsen surgical outcomes, and prolong recovery. Importantly, however, previous studies did not stratify by diversion type. We performed a population-based analysis of preoperative oral antibiotic BRs (OABRs) with RC, alongside subgroup analyses to compare outcomes by diversion type. Methods: RCs performed from 2019-2020 were identified using the new NSQIP Cystectomy-Targeted PUF. Captured variables included OABR, diversion type, demographics, comorbidities, and perioperative outcomes. Univariate analysis with two tailed chi square and t tests was performed to compare baseline characteristics, 30-day mortality, and complications. Multivariable logistic regression with stepwise-backward-elimination (p &gt; 0.25) adjusted for mechanical BRs, operative approach, comorbidities, functional status, demographics, ASA class, labs, and staging. Results: In total, 3,894 RCs were performed, of which 357 (9.2%) included OABR. There were no significant baseline differences between the OABR and the non-OABR cohorts. On univariate analysis, OABR patients had increased operative time, length of stay (LOS), minor complications, and bleeds. On subgroup analysis, ileal conduit patients experienced higher rates of the 4 aforementioned outcomes plus deep wound infections and NGT use. However, the continent diversion subgroup was not associated with increased operative time, LOS, or any complications. Continent diversion had significantly lower rates of sepsis and ureteral fistula formation. Upon multivariable adjustment, OABR was not associated with increased rates of any complications across any subgroup. OABR did confer significantly decreased odds of sepsis in continent diversion patients. Conclusions: Supporting ERAS recommendations, this study showed that pre-RC OABRs do not improve outcomes and increase LOS for ileal conduits. However, this study uniquely included continent diversions, such as neobladders and Indiana pouches. Importantly, in continent diversion patients, OABR did not increase LOS or complications while decreasing sepsis rates. These findings suggest possible utility of OABR before RC with continent diversion.
Prognostic value of DNA damage repair and tolerance factors in patients with muscle-infiltrating urothelial carcinoma.
Authors: Patrik Palacka, Andrea Holickova, Jan Roska, Miroslava Vallova, Csaba Biro, Jan Slopovsky, Eveline Orasova, Jozef Mardiak, Karol Kajo, Miroslav Chovanec
Journal: Journal of Clinical Oncology (2023)

e16615 Background: Cisplatin (CDDP) is the key agent in treatment of muscle-infiltrating urothelial carcinomas (MIUCs). However, around a half of patients do not respond to combined chemotherapy based on this agent what might be caused by an increased capacity to repair CDDP-induced DNA damage. The objective of this study was to determine the levels of selected DNA repair and tolerance factors in patients with MIUC to reveal their potential prognostic value. Methods: We have evaluated the bladder tumors from 86 subjects reviewed by trained pathologists. Median age was 67 years (range 37-84 years), 75.6% were males. All patients had MIUCs. To detect the XPA, XPF, POLI, REV3L, and POLH levels in primary tumors, immunohistochemistry was used. Study population was divided into two groups by positivity defined as 76-100% (negative vs positive tumors). Overall survival (OS) was estimated by the Kaplan-Meier method and compared with the log-rank test. Results: At median follow-up of 20.6 months (1.0-212.5 months), 86.1% of patients died. Median OS of subjects with tumors stained negative for XPA, XPF, REV3L, and POLH did not differ significantly from patients with positive staining for these proteins, with hazard ratios (HRs) being 0.61, 0.62, 0.98, and 0.72, respectively. Patients with tumor negative for POLI expression had significantly ( p = 0.0334) better median OS of 23.5 months (range 17.3-47.3 months) compared to subjects with tumor stained positive for expression of this protein [median OS of 17.6 months (range 13.6-21.3 months)] (HR = 0.61, 95%, CI 0.39-0.97). Conclusions: In this study, we showed a clear correlation between higher POLI expression in primary tumor tissue and inferior outcome in MIUC patients. Hence, we believe that the expression level of POLI might represent a prognostic biomarker and potentially constitute promising therapeutic target.